Each year, cigarette smoking costs an estimated 418,000 American lives. Smoking cessation reduces this work, but is extremely difficult because smoking is maintained by factors such as nicotine withdrawal, tobacco's direct effects, and smoking-related stimuli that can control smoker's behavior. Current cessation methods address these factors. Nicotine replacement treatment suppresses withdrawal and/or blunts the effects of cigarettes. Behavioral treatments reduce the influence of smoking-related stimuli. Nonetheless, about 70% of smokers who try to quit, fail. Improving smoking subgroups, such as men and women. Treatment studies demonstrate that quitting is more difficult for women. There is no definitive explanation for this sex difference, but it may involve a differential response to nicotine replacement treatment and/or smoking- related stimuli. For women, nicotine replacement may be less effective at suppressing withdrawal symptoms (Hypothesis 1) or at blunting the effects of cigarettes smoked during a quit attempt (Hypothesis 2). Women may also be more sensitive to smoking-related stimuli, such as the taste, sight, and smell of cigarette smoke (Hypothesis 3). These hypotheses can be examined efficiently in the clinical laboratory. Strengths of this setting include control over extraneous variables, repeated measure designs that yield nicotine dose effect curves, and validated tools for measuring puff topography, tobacco withdrawal, and the direct effects of nicotine and/or cigarettes. Three such studies are proposed. In each study, 45 men and 45 women non-treatment seeking smokers will participate in 4 double blind, randomly ordered, 6.5-hour sessions. Objectively verified cigarette abstinence will be required before each session. Studies 1 and 2 will compare, in men and women, the nicotine dose response functions for suppression for tobacco withdrawal and for blunting the effects of cigarettes. Study 3 will compare, in men and women, the effects of smoking-related stimuli (denicotinized cigarettes). Thus hypotheses 1, 2, and 3 will be addressed in separate studies in this 5-year project. The project will help to elucidate the mechanism underlying oft-reported sex differences in smoking cessation and may help tailor combined pharmacological and behavioral treatments that maximize the likelihood of cessation for men and women smokers. Given the overwhelming costs of cigarette smoking and the dramatic reduction in those costs when smokers quit smoking, improving the treatment options for all American smokers is essential.